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Background: The identification of chemical–target interaction is key to pharmaceutical research and development, but the unclear materials basis and complex mechanisms of traditional medicine (TM) make it difficult, especially for low-content chemicals which are hard to test in experiments. In this research, we aim to apply the node2vec algorithm in the context of drug-herb interactions for expanding potential targets and taking advantage of molecular docking and experiments for verification. Methods: Regarding the widely reported risks between cardiovascular drugs and herbs, Salvia miltiorrhiza (Danshen, DS) and Ligusticum chuanxiong (Chuanxiong, CX), which are widely used in the treatment of cardiovascular disease (CVD), and approved drugs for CVD form the new dataset as an example. Three data groups DS-drug, CX-drug, and DS-CX-drug were applied to serve as the context of drug-herb interactions for link prediction. Three types of datasets were set under three groups, containing information from chemical-target connection (CTC), chemical-chemical connection (CCC) and protein–protein interaction (PPI) in increasing steps. Five algorithms, including node2vec, were applied as comparisons. Molecular docking and pharmacological experiments were used for verification. Results: Node2vec represented the best performance with average AUROC and AP values of 0.91 on the datasets "CTC, CCC, PPI". Targets of 32 herbal chemicals were identified within 43 predicted edges of herbal chemicals and drug targets. Among them, 11 potential chemical-drug target interactions showed better binding affinity by molecular docking. Further pharmacological experiments indicated caffeic acid increased the thermal stability of the protein GGT1 and ligustilide and low-content chemical neocryptotanshinone induced mRNA change of FGF2 and MTNR1A, respectively. Conclusions: The analytical framework and methods established in the study provide an important reference for researchers in discovering herb–drug interactions, alerting clinical risks, and understanding complex mechanisms of TM. [ABSTRACT FROM AUTHOR]

Background: This study aims to evaluate the value of p16INK4a immunostaining for high-grade squamous intraepithelial lesions in human papillomavirus-negative patients in Beijing, China.Methods: In this study, we evaluated the value of p16INK4a immunostaining, as well as cytology and colposcopy, for predicting high-grade squamous intraepithelial lesions (HSIL) in human papillomavirus (HPV)-negative patients by comparing the methods with the haematoxylin and eosin (H&E) staining pathological diagnosis of HPV-negative patients.Results: Of 122 patients negative for the high-risk HPV (hrHPV) subtype, 26 (21.3%) underwent colposcopically directed multiple punch cervical biopsies with H&E pathological diagnoses of HSIL and above (HSIL+), 11 patients (9.0%) had cervical intraepithelial neoplasia (CIN)2, nine patients (7.4%) had CIN3 and six patients (4.9%) had infiltrating carcinomas. Cytology, colposcopy and p16INK4a immunostaining had 52.4%, 38.5% and 92.3% sensitivity, respectively, and 76.2%, 94.8% and 99% specificity, respectively. The positive predictive value of the cytology, colposcopy and p16INK4a immunostaining was 31.4%, 66.7% and 96%, respectively, and the negative predictive value was 88.5%, 85.1% and 97.9%, respectively. Compared with H&E staining, the kappa of the cytology, colposcopy and p16INK4a immunostaining was 0.327, 0.323 and 0.926, respectively.Conclusion: Positive p16INK4a immunostaining is very strongly consistent with an H&E diagnosis of CIN2+, and it can be used as an objective detection index for HSIL+ diagnoses of HPV-negative patients with CIN2+. [ABSTRACT FROM AUTHOR]

Background: The ras genes play an important role in the development and progression of human tumours. Neutralizing Ras proteins in the cytoplasm could be an effective approach to blocking ras signalling. In this study, we prepared anti-p21Ras single chain fragment variable antibody (scFv) and investigated its immunoreactivity with human tumours.Methods: The coding sequences of H-ras, K-ras, and N-ras were separately ligated into the vector pET-28a(+). Then, recombinant expressing plasmids were induced by IPTG for p21Ras expression in E. coli. Hybridoma cell lines producing anti-p21Ras monoclonal antibodies were isolated using wildtype p21Ras proteins as immunogens. Anti-p21Ras scFv antibody was prepared from the hybridoma by the phage scFv display method. The immunoreactivity of the anti-p21Ras monoclonal antibody and the scFv antibody was identified by ELISA and immunocytochemistry.Results: We prokaryotically expressed wildtype H-p21Ras, K-p21Ras and N-p21Ras and generated the hybridoma cell line KGH-R1, producing anti-p21Ras monoclonal antibodies. It was demonstrated that KGH-R1 monoclonal antibody could recognize wildtype and mutated H-p21Ras, K-p21Ras and N-p21Ras in human tumour cell lines. In all 14 types of primary human cancer tissues tested, the monoclonal antibody presented strong immunoreactivity but showed weak or negative immunoreactivity in the corresponding normal tissues. Subsequently, we prepared anti-p21Ras scFv from hybridoma KGH-R1, which showed the same immunoreactivity as the original monoclonal antibody. Sequence analysis demonstrated that the nucleotides and amino acids of the scFv exhibited an approximately 50 % difference from the anti-p21Ras scFv reported previously.Conclusions: This study presents a novel anti-p21Ras scFv antibody. Our data suggest that the scFv may be useful for ras signalling blockage and may be a potential therapeutic antibody for ras-derived tumours. [ABSTRACT FROM AUTHOR]

Background: MicroRNAs are stable and easy to detect in plasma. The plasma levels of microRNAs are often changed in disease conditions, including cancer. This makes circulating microRNAs a novel class of biomarkers for cancer diagnosis. Analyses of online microRNA data base revealed that expression level of three microRNAs, microRNA-24 (miR-24), microRNA-320a (miR-320a), and microRNA-423-5p (miR-423-5p) were down-regulated in colorectal cancer (CRC). However, whether the plasma level of these three microRNAs can serve as biomarkers for CRC diagnosis and prognosis is not determined. Methods: Plasma samples from 223 patients with colorectal related diseases (111 cancer carcinoma, 59 adenoma, 24 colorectal polyps and 29 inflammatory bowel disease) and 130 healthy controls were collected and subjected to reverse transcription-quantitative real time PCR (RT-qPCR) analyses for the three microRNAs. In addition, plasma samples from 43 patients were collected before and after surgical treatment for the same RT-qPCR analyses. Results: The concentrations of plasma miR-24, miR-320a and miR-423-5p were all decreased in patients with CRC and benign lesions (polyps and adenoma) compared with healthy controls, but increased in inflammatory bowel disease (IBD). The sensitivity of miR-24, miR-320a and miR-423-5p for early stage of CRC were 77.78 %, 90.74 %, and 88.89 %, respectively. Moreover, the plasma concentration of the three microRNAs was increased in patients after the surgery who had clinical improvement. Conclusions: The plasma levels of miR-24, miR-320a, and miR-423-5p have promising potential to serve as novel biomarkers for CRC detection, especially for early stage of CRC, which are superior to the currently used clinical biomarkers for CRC detection, such as CEA and CA19-9. Further efforts to develop the three microRNAs as biomarkers for early CRC diagnosis and prediction of surgical treatment outcomes are warrant. [ABSTRACT FROM AUTHOR]

Background: Alternaria solani is a known air-born deuteromycete fungus with a polycyclic life cycle and is the causal agent of early blight that causes significant yield losses of potato worldwide. However, the molecular mechanisms underlying the conidiation and pathogenicity remain largely unknown. Results: We produced a high-quality genome assembly of A. solani HWC-168 that was isolated from a major potato-producing region of Northern China, which facilitated a comprehensive gene annotation, the accurate prediction of genes encoding secreted proteins and identification of conidiation-related genes. The assembled genome of A. solani HWC-168 has a genome size 32.8 Mb and encodes 10,358 predicted genes that are highly similar with related Alternaria species including Alternaria arborescens and Alternaria brassicicola. We identified conidiation-related genes in the genome of A. solani HWC-168 by searching for sporulation-related homologues identified from Aspergillus nidulans. A total of 975 secreted protein-encoding genes, which might act as virulence factors, were identified in the genome of A. solani HWC-168. The predicted secretome of A. solani HWC-168 possesses 261 carbohydrate-active enzymes (CAZy), 119 proteins containing RxLx[EDQ] motif and 27 secreted proteins unique to A. solani. Conclusions: Our findings will facilitate the identification of conidiation- and virulence-related genes in the genome of A. solani. This will permit new insights into understanding the molecular mechanisms underlying the A. solani-potato pathosystem and will add value to the global fungal genome database. [ABSTRACT FROM AUTHOR]

Background: This study aimed to investigate the mechanism of the probiotic VSL#3 in acute alcoholic intestinal injury, and evaluate the effect of VSL#3, glutamine,VSL#3+glutamine and heat-killed VSL#3 therapy in a rat model.Methods: Six- to eight-week-old male wild-type rats were divided into seven groups. To establish the acute alcohol liver disease model, rats received three doses of corn starch dissolved in PBS/40% alcohol administered intra-gastrically every 12 hours. Treatment groups received an intra-gastric dose of VSL#3, Glutamine, heat-killed VSL#3, or VSL#3+Glutamine 30 minutes prior to alcohol administration. The placebo group was treated with PBS prior to alcohol administration. TNFα and endotoxin in plasma was measured by ELISA and Tachypleus Ameboctye Lysate assays, and electron microscopy, Western blotting, and reverse transcription polymerase chain reaction were used to identify the mechanisms of VSL#3 in the regulation of epithelial permeability.Results: First, compared with control group, endotoxin and TNFα in alcohol group was obviously high. At the same time, in VSL#3 group,the expression of endotoxin and TNFα obviously lower than the alcohol group. And the trends of the expression of tight junction proteins in these groups were reversed with the change of endotoxin and TNFα. Second, compared the groups of VSL#3 with glutamine,VSL#3+glutamine and heat-killed VSL#3,we found that both VSL#3 and heat-killed VSL#3, glutamine were as effective as VSL#3+glutamine in the treatment of acute alcohol liver disease, the expression of endotoxin and TNFα were lower than the alcohol group, and tight junction proteins were higher than the alcohol group whereas the expression of tight junction proteins were higher in VSL#3 + glutamine group than either agent alone, but have no significant difference.Conclusion: We conclude that VSL#3 treatment can regulate the ecological balance of the gut microflora, preventing passage of endotoxin and other bacterial products from the gut lumen into the portal circulation and down-regulating the expression of TNFα, which could otherwise down-regulate the expression of tight junction proteins and increase epithelial permeability. [ABSTRACT FROM AUTHOR]

Background: Choosing the appropriate antipsychotic drug (APD) treatment for patients with schizophrenia (SCZ) can be challenging, as the treatment response to APD is highly variable and difficult to predict due to the lack of effective biomarkers. Previous studies have indicated the association between treatment response and genetic and epigenetic factors, but no effective biomarkers have been identified. Hence, further research is imperative to enhance precision medicine in SCZ treatment., Methods: Participants with SCZ were recruited from two randomized trials. The discovery cohort was recruited from the CAPOC trial (n = 2307) involved 6 weeks of treatment and equally randomized the participants to the Olanzapine, Risperidone, Quetiapine, Aripiprazole, Ziprasidone, and Haloperidol/Perphenazine (subsequently equally assigned to one or the other) groups. The external validation cohort was recruited from the CAPEC trial (n = 1379), which involved 8 weeks of treatment and equally randomized the participants to the Olanzapine, Risperidone, and Aripiprazole groups. Additionally, healthy controls (n = 275) from the local community were utilized as a genetic/epigenetic reference. The genetic and epigenetic (DNA methylation) risks of SCZ were assessed using the polygenic risk score (PRS) and polymethylation score, respectively. The study also examined the genetic-epigenetic interactions with treatment response through differential methylation analysis, methylation quantitative trait loci, colocalization, and promoter-anchored chromatin interaction. Machine learning was used to develop a prediction model for treatment response, which was evaluated for accuracy and clinical benefit using the area under curve (AUC) for classification, R 2 for regression, and decision curve analysis., Results: Six risk genes for SCZ (LINC01795, DDHD2, SBNO1, KCNG2, SEMA7A, and RUFY1) involved in cortical morphology were identified as having a genetic-epigenetic interaction associated with treatment response. The developed and externally validated prediction model, which incorporated clinical information, PRS, genetic risk score (GRS), and proxy methylation level (proxyDNAm), demonstrated positive benefits for a wide range of patients receiving different APDs, regardless of sex [discovery cohort: AUC = 0.874 (95% CI 0.867-0.881), R 2  = 0.478; external validation cohort: AUC = 0.851 (95% CI 0.841-0.861), R 2  = 0.507]., Conclusions: This study presents a promising precision medicine approach to evaluate treatment response, which has the potential to aid clinicians in making informed decisions about APD treatment for patients with SCZ. Trial registration Chinese Clinical Trial Registry ( https://www.chictr.org.cn/ ), 18. Aug 2009 retrospectively registered: CAPOC-ChiCTR-RNC-09000521 ( https://www.chictr.org.cn/showproj.aspx?proj=9014 ), CAPEC-ChiCTR-RNC-09000522 ( https://www.chictr.org.cn/showproj.aspx?proj=9013 )., (© 2023. The Author(s).)

Background: Schizophrenia is a highly heritable chronic mental disorder with significant abnormalities in brain function. The neurodevelopmental hypothesis proposes that schizophrenia originates in the prenatal period due to impairments in neuronal developmental processes such as migration and arborization, leading to abnormal brain maturation. Previous studies have identified multiple promising candidate genes that drive functions in neurodevelopment and are associated with schizophrenia. However, the molecular mechanisms of how they exert effects on the pathophysiology of schizophrenia remain largely unknown., Results: In our research, we identified growth arrest specific gene 7 (GAS7) as a schizophrenia risk gene in two independent Han Chinese populations using a two-stage association study. Functional experiments were done to further explore the underlying mechanisms of the role of Gas7 in cortical development. In vitro, we discovered that Gas7 contributed to neurite outgrowth through the F-BAR domain. In vivo, overexpression of Gas7 arrested neuronal migration by increasing leading process branching, while suppression of Gas7 could inhibit neuronal migration by lengthening leading processes. Through a series of behavioral tests, we also found that Gas7-deficient mice showed sensorimotor gating deficits., Conclusions: Our results demonstrate GAS7 as a susceptibility gene for schizophrenia. Gas7 might participate in the pathogenesis of schizophrenia by regulating neurite outgrowth and neuronal migration through its C-terminal F-BAR domain. The impaired pre-pulse inhibition (PPI) of Gas7-deficient mice might mirror the disease-related behavior in schizophrenia.

Background: Loss of function mutations in RAB18, has been identified in patients with the human neurological and developmental disorder Warburg Micro syndrome. However, the function of RAB18 in brain remains unknown., Results: In this study, we report that RAB18 is a critical regulator of neuronal migration and morphogenesis. Using in utero electroporation suppression of RAB18 in the mouse brain impairs radial migration. Overexpression of dominant negative RAB18 or disruption of RAB3GAP (RAB18GEF) also results in delayed neuronal migration in the developing mouse cortex and inhibition of neurite growth in vitro. Moreover, loss of RAB18 induces an acceleration of N-cadherin degradation by lysosomal pathway resulting in the decrease of surface level of N-cadherin on neurons., Conclusions: RAB18 regulates neuronal migration and morphogenesis during development. Our findings highlight the critical role of RAB3GAP-RAB18 pathway in the developing cerebral cortex and might explain some of clinical features observed in patients with Warburg Micro syndrome.

Background: G-protein receptor kinase 5 (GRK5) Gln41 > Leu and β1-adrenergic receptor (ADRB1) Arg389 > Gly polymorphisms presented the different distribution of genotype frequencies between Caucasian American and African American, and produced the difference in β-blocker treatment effect among them with systolic heart failure (SHF)., Objective: This study sought to identify the distributed characteristics of these variant genotypes in Chinese population, and influence of GRK5 and ADRB1 polymorphisms on SHF morbidity and β-blocker treatment effect in patients with SHF., Methods: This study was based on cross-sectional survey data. 1794 and 1718 subjects' ADRB1 and GRK5 gene sequencing (sanger method) data were achieved respectively. Blood samples collection, clinical laboratory detection, electrocardiogram and echocardiography examinations were performed. Medication usage was confirmed at in-hospital visits or the questionnaire by personal interview., Results: GRK5 Leu41Leu genotype was not found in our Chinese population. In non-SHF population, allele frequencies of GRK5 Gln41 and Leu41 were 2782 (0.992) and 22 (0.008) (Hardy-Weinberg equilibrium test χ(2) = 0.088, P = 0.767), and allele frequencies of ADRB1 Arg389 and Gly389 were 2127 (0.715) and 849 (0.285) (χ(2) = 0.272, P = 0.602). In SHF patients, allele frequencies of Gln41 and Leu41 were 446 (0.991) and 4 (0.009) (χ(2) = 0.018, P = 0.893), and allele frequencies of Arg389 and Gly389 were 331 (0.726) and 125 (0.274) (χ(2) = 1.892, P = 0.169). Further in logistic regression model, these ADRB1 and GRK5 variants were not significantly independently associated with the risk of SHF morbidity. Those carrying genotype ADRB1 Gly389Gly did not reduce significantly the risk of SHF morbidity after β-blocker therapy., Conclusions: GRK5 Leu41Leu genotype was not found in our Chinese population, neither ADRB1 nor GRK5 variants presented independently associated with the risk of SHF morbidity, most ADRB1 and GRK5 polymorphisms did decrease significantly the risk of SHF morbidity after β-blocker therapy except for those carrying genotype ADRB1 Gly389Gly.

Background: Numerous single nucleotide polymorphisms (SNPs) associated with complex diseases have been identified by genome-wide association studies (GWAS) and expression quantitative trait loci (eQTLs) studies. However, few of these SNPs have explicit biological functions. Recent studies indicated that the SNPs within the 3'UTR regions of susceptibility genes could affect complex traits/diseases by affecting the function of miRNAs. These 3'UTR SNPs are functional candidates and therefore of interest to GWAS and eQTL researchers., Description: We developed a publicly available online database, MirSNP (http://cmbi.bjmu.edu.cn/mirsnp), which is a collection of human SNPs in predicted miRNA-mRNA binding sites. We identified 414,510 SNPs that might affect miRNA-mRNA binding. Annotations were added to these SNPs to predict whether a SNP within the target site would decrease/break or enhance/create an miRNA-mRNA binding site. By applying MirSNP database to three brain eQTL data sets, we identified four unreported SNPs (rs3087822, rs13042, rs1058381, and rs1058398), which might affect miRNA binding and thus affect the expression of their host genes in the brain. We also applied the MirSNP database to our GWAS for schizophrenia: seven predicted miRNA-related SNPs (p < 0.0001) were found in the schizophrenia GWAS. Our findings identified the possible functions of these SNP loci, and provide the basis for subsequent functional research., Conclusion: MirSNP could identify the putative miRNA-related SNPs from GWAS and eQTLs researches and provide the direction for subsequent functional researches.

Background: Ghrelin (GHRL) is a pivotal peptide regulator of food intake, energy balance, and body mass. Weight gain (WG) is a common side effect of the atypical antipsychotics (AAPs) used to treat schizophrenia (SZ). Ghrelin polymorphisms have been associated with pathogenic variations in plasma lipid concentrations, blood pressure, plasma glucose, and body mass index (BMI). However, it is unclear whether GHRL polymorphisms are associated with WG due to AAPs. Furthermore, there is no evidence of an association between GHRL polymorphisms and SZ or the therapeutic response to AAPs. We explored these potential associations by genotyping GHRL alleles in SZ patients and controls. We also examined the relation between these SNPs and changes in metabolic indices during AAP treatment in SZ subgroups distinguished by high or low therapeutic response., Methods: Four SNPs (Leu72Met, -501A/C, -604 G/A, and -1062 G > C) were genotyped in 634 schizophrenia patients and 606 control subjects., Results: There were no significant differences in allele frequencies, genotype distributions, or the distributions of two SNP haplotypes between SZ patients and healthy controls (P > 0.05). There was also no significant difference in symptom reduction between genotypes after 8 weeks of AAP treatment as measured by positive and negative symptom scale scores (PANSS). However, the -604 G/A polymorphism was associated with a greater BMI increase in response to AAP administration in both APP responders and non-responders as distinguished by PANSS score reduction (P < 0.001). There were also significant differences in WG when the responder group was further subdivided according to the specific AAP prescribed (P < 0.05)., Conclusions: These four GHRL gene SNPs were not associated with SZ in this Chinese Han population. The -604 G/A polymorphism was associated with significant BW and BMI increases during AAP treatment. Patients exhibiting higher WG showed greater improvements in positive and negative symptoms than patients exhibiting lower weight gain or weight loss.

Background: Disrupted-in-Schizophrenia 1 (DISC1) gene is one of the most promising candidate genes for major mental disorders. In a previous study, a Finnish group demonstrated that DISC1 polymorphisms were associated with autism and Asperger syndrome. However, the results were not replicated in Korean population. To determine whether DISC1 is associated with autism in Chinese Han population, we performed a family-based association study between DISC1 polymorphisms and autism., Methods: We genotyped seven tag single nucleotide polymorphisms (SNPs) in DISC1, spanning 338 kb, in 367 autism trios (singleton and their biological parents) including 1,101 individuals. Single SNP association and haplotype association analysis were performed using the family-based association test (FBAT) and Haploview software., Results: We found three SNPs showed significant associations with autism (rs4366301: G>C, Z=2.872, p=0.004; rs11585959: T>C, Z=2.199, p=0.028; rs6668845: A>G, Z=2.326, p=0.02). After the Bonferroni correction, SNP rs4366301, which located in the first intron of DISC1, remained significant. When haplotype were constructed with two-markers, three haplotypes displayed significant association with autism. These results were still significant after using the permutation method to obtain empirical p values., Conclusions: Our study provided evidence that the DISC1 may be the susceptibility gene of autism. It suggested DISC1 might play a role in the pathogenesis of autism.

Background: Recent research has implicated that mutations in the neurexin-1 (NRXN1) gene on chromosome 2p16.3 might play a role in schizophrenia, autism, and nicotine dependence. In order to explore the association of NRXN1 polymorphisms with schizophrenia, we made a case-control association study in Chinese Han population., Methods: We examined six tag single nucleotide polymorphisms (SNPs) spanning 116.7 kb of NRXN1 in 768 schizophrenic patients and 738 healthy control subjects. The association of NRXN1 polymorphisms with schizophrenia and the age-at-onset of this disease were explored., Results: Our results showed that four SNPs of NRXN1 gene were significantly associated with schizophrenia (rs10490168: G > A, p = 0.017; rs2024513: A > G, p = 0.006; rs13382584: T > C, p = 0.009; and rs1558852: G > A, p = 0.031). Furthermore, the association of SNP rs2024513 with schizophrenia remained significance after the Bonferroni correction. Haplotypes consisting of above six SNPs also showed significantly associated with schizophrenia (global chi-square = 14.725, p = 0.022). A protective haplotype AGTGCA remained associated with schizophrenia, even after 10,000 permutation tests (empirical p-value = 0.043). However, we did not find any association with age-at-onset of schizophrenia with NRXN1 polymorphisms., Conclusions: Our findings suggest that NRXN1 might represent a major susceptibility gene for schizophrenia in Chinese Han population.

Background: Autism, a heterogeneous disease, is described as a genetic psychiatry disorder. Recently, abnormalities at the synapse are supposed to be important for the etiology of autism.SHANK3 (SH3 and multiple ankyrin repeat domains protein) gene encodes a master synaptic scaffolding protein at postsynaptic density (PSD) of excitatory synapse. Rare mutations and copy number variation (CNV) evidence suggested SHANK3 as a strong candidate gene for the pathogenesis of autism., Methods: We performed an association study between SHANK3 gene polymorphisms and autism in Chinese Han population. We analyzed the association between five single nucleotide polymorphisms (SNPs) of the SHANK3 gene and autism in 305 Chinese Han trios, using the family based association test (FBAT). Linkage disequilibrium (LD) analysis showed the presence of LD between pairwise markers across the locus. We also performed mutation screening for the rare de novo mutations reported previously., Results: No significant evidence between any SNPs of SHANK3 and autism was observed. We did not detect any mutations described previously in our cohort., Conclusion: We suggest that SHANK3 might not represent a major susceptibility gene for autism in Chinese Han population.